JPH06504549A - (2R,3S)-β-phenylisoserine, its salt, its production and its use - Google Patents
(2R,3S)-β-phenylisoserine, its salt, its production and its useInfo
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- JPH06504549A JPH06504549A JP4504007A JP50400792A JPH06504549A JP H06504549 A JPH06504549 A JP H06504549A JP 4504007 A JP4504007 A JP 4504007A JP 50400792 A JP50400792 A JP 50400792A JP H06504549 A JPH06504549 A JP H06504549A
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- phenylisoserine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
Abstract
Description
【発明の詳細な説明】 （２Ｒ，３Ｓ）−β−フェニルイソセリン、その塩、その製造及びその利用 本発明は式： ＋７） （２Ｒ，３Ｓ）−β−フェニルイソセリン、ならびにそのアルカリ金属 又はアルカリ土類金属塩及び窒素性塩基とのその塩、その製造及び治療的活性生 成物の製造へのその利用に関する。[Detailed description of the invention] (2R,3S)-β-phenylisoserine, its salt, its production and its use The present invention is based on the formula: +7) (2R,3S)-β-phenylisoserine and its alkali metals or alkaline earth metal salts and their salts with nitrogenous bases, their preparation and therapeutically active forms. Concerning its use in the manufacture of products.
β−フェニルイソセリンの（２Ｒ，３Ｒ）、（２Ｓ、３Ｓ）及び（２Ｓ、３Ｒ） 異性体は科学文献において、例えばＥ、Ｋａｍａｎｄｉ ｅｔ ａｌ、、Ａｒｃ ｈ、Ｐｈａｒｍａｚ、、３０７，８７１−８７８ （１９７４Ｌ Ｅ、Ｋａｍａ ｎｄｉ ｅｔ ａｌ、、Ａｒｃｈ、Ｐｈａｒｍａｚ、、３０８．１３５−１４１ （１９７５）又はに、Ｈａｒａｄａａｎｄ Ｙ、Ｎａｋａｊ ｉｍａ、Ｂｕｌ ｌ、Ｃｈｅｍ、Ｓａｃ、Ｊａｐａｎ、４７．２９１１−２９１２ （１９７４） などの論文において既知であるが、（２Ｒ，３Ｓ）−β−フェニルイソセリンは エステルの形態以外ではまだ記載されたことがないと思われる［Ｈ，ＨＱｎｉｇ ｅｔ本発明に従い、好ましくはアルカリ金属又はアルカリ土類金属（ナトリウ ム、カリウム、カルシウム）塩、アンモニウム塩あるいは窒素性塩基（α−メチ ルベンジルアミン、ピリジン）との塩の形態の（２Ｒ，３Ｒ）−β−フェニルグ リシド酸へのアンモニア溶液の作用により、場合により塩の形態の（２Ｒ，３Ｓ ）−β−フェニルイソセリンを得ることができる。(2R, 3R), (2S, 3S) and (2S, 3R) of β-phenylisoserine Isomers are described in the scientific literature, e.g. by E., Kamandi et al., Arc h, Pharmaz, 307, 871-878 (1974L E, Kama ndi et al, Arch, Pharmaz, 308.135-141 (1975) or Harada and Y, Nakaj ima, Bul l, Chem, Sac, Japan, 47.2911-2912 (1974) It is known from papers such as (2R,3S)-β-phenylisoserine It seems that it has never been described in any form other than the ester form [H, HQnig et according to the present invention, preferably alkali metals or alkaline earth metals (sodium salts, ammonium salts or nitrogenous bases (alpha-methyl, potassium, calcium), (2R,3R)-β-phenyl in the form of a salt with (rubenzylamine, pyridine) By the action of ammonia solution on lysidic acid, (2R,3S )-β-phenylisoserine can be obtained.
一般にこの方法は、場合によりメタノールなどの有機溶媒と混合した水中で行う 。水中で行うのが好ましい。This method is generally performed in water, optionally mixed with an organic solvent such as methanol. . Preferably, it is carried out underwater.
、 この方法を行うために、（２Ｒ，３Ｒ）−β−フェニルグリシド酸に対して 過剰のアンモニアを用いることが必要である。一般に（２Ｒ，３Ｒ）−β−フェ ニルグリシド酸の１モル当たり１０−１００モルのアンモニア、好ましくは５０ −８０モルのアンモニアを用いる。, To carry out this method, for (2R,3R)-β-phenylglycidic acid It is necessary to use excess ammonia. Generally (2R,3R)-β-fe 10-100 moles of ammonia per mole of nylglycidic acid, preferably 50 -80 mol of ammonia are used.
アンモニアは、２５℃近辺の温度で２０−３２％（Ｗ／Ｗ）の濃度の溶液などの 濃水溶液の形態で用いるのが好ましい。Ammonia can be used as a solution at a concentration of 20-32% (W/W) at a temperature around 25°C. Preferably, it is used in the form of a concentrated aqueous solution.
この方法は０−１００℃、好ましくは４０〜６０℃の温度で行う。一般に方法は 大気圧下、又は代わりに６０℃にて２．５バールの近辺の自己圧力下で行う。The process is carried out at temperatures of 0-100°C, preferably 40-60°C. Generally the method is It is carried out under atmospheric pressure or alternatively under autogenous pressure in the vicinity of 2.5 bar at 60°C.
反応の速度を増すために、塩化アンモニウム又は炭酸水素アンモニウムなどのア ンモニウム塩の存在下で行うのが特に有利である。選択性を維持しながら反応速 度を増すことができる炭酸水素アンモニウムの使用が好ましい。一般にβ−フェ ニルグリシド酸の使用量に対して化学量論量のアンモニウム塩を用いる。To speed up the reaction, add an atom such as ammonium chloride or ammonium bicarbonate. Particular preference is given to working in the presence of ammonium salts. Reaction speed while maintaining selectivity Preference is given to using ammonium bicarbonate, which can be highly concentrated. Generally β-fe A stoichiometric amount of ammonium salt is used relative to the amount of nylglycidic acid used.
一般にこの方法は（２Ｒ，３Ｒ）−β−フェニルグリシド酸とα−メルアミンの 塩への化学量論量の塩基（水酸化ナトリウム、水酸化カリウム）の作用により得 られるアルカリ金ｇＲ（ナトリウム、カリウム）塩、又は過剰のアンモニア溶液 による（２Ｒ，３Ｒ）−β−フェニルグリシド酸とα−メチルベンジルアミンの 塩の置換により得られるアンモニウム塩の使用も可能である。後者の場合、トル エンなどの適した有機溶媒を用いたα−メチルベンジルアミンの連続又は半一連 続抽出による置換を選ぶこともできる。Generally, this method consists of (2R,3R)-β-phenylglycidic acid and α-melamine. obtained by the action of stoichiometric amounts of bases (sodium hydroxide, potassium hydroxide) on the salt. alkali gold gR (sodium, potassium) salts or excess ammonia solution of (2R,3R)-β-phenylglycidic acid and α-methylbenzylamine by It is also possible to use ammonium salts obtained by salt substitution. In the latter case, Tor Continuous or semi-sequential preparation of α-methylbenzylamine using a suitable organic solvent such as You can also choose to replace by subsequent extraction.
（２Ｒ，３Ｒ）−β−フェニルグリシド酸のアンモニウム塩の使用が特に有利で あり、これは位置選択的及び立体選択的なアンモニアによる開環を可能にする。The use of ammonium salts of (2R,3R)-β-phenylglycidic acid is particularly advantageous. , which allows regioselective and stereoselective ring opening with ammonia.
（２Ｒ，３Ｒ）−β−フェニルグリシド酸にアンモニアを作用させる方法にかか わらず、（２Ｒ，３８）−β−フェニルイソセリンは以下の方法の１つに従って 単離することができる：１）過剰のアンモニアを減圧下で除去して水溶液中の（ ２Ｒ，３Ｓ）−β−フェニルグリシド酸のアンモニウム塩を得ることができる。Regarding the method in which ammonia acts on (2R,3R)-β-phenylglycidic acid. However, (2R,38)-β-phenylisoserine can be prepared according to one of the following methods: Can be isolated: 1) Excess ammonia is removed under reduced pressure to remove ( The ammonium salt of 2R,3S)-β-phenylglycidic acid can be obtained.
無機強酸の添加後、（２Ｒ，３Ｓ）−β−フェニルイソセリンが沈澱し、濾過に より分離する。又は ２）減圧下におけるアンモニアの除去の前、その間、あるいはその後にアルカリ 金属塩基（水酸化ナトリウム、水酸化カリウム）又はアルカリ土類金属塩基（生 石灰又は消石灰）を添加することができる；形成した塩は場合によりアセトンな どの有機溶媒の添加後に沈澱する。それにより得られたアルカリ金属又はアルカ リ土類金属塩を濾過により分離する。After addition of strong inorganic acid, (2R,3S)-β-phenylisoserine precipitates and is not filtered. Separate more. or 2) alkali before, during, or after removal of ammonia under reduced pressure; Metal bases (sodium hydroxide, potassium hydroxide) or alkaline earth metal bases (raw) lime or slaked lime); the salt formed may optionally be mixed with acetone or Precipitation occurs after addition of any organic solvent. The alkali metal or alkali metal obtained thereby The lithium metal salts are separated by filtration.
ナトリウムの添加により飽和するのが有利である。Advantageously, it is saturated by addition of sodium.
（２Ｒ，３Ｒ）−β−フェニルグリシド酸はＪ−Ｎ、Ｄｅｎｉｓ ｅｔ ａｌ、 、Ｊ、Ｏｒｇ、Ｃｈｅｍ、、５１．４６−５０ （１９８６）に記載の条件下で 製造することができる。(2R,3R)-β-phenylglycidic acid was prepared by J-N, Denis et al. , J. Org. Chem., 51.46-50 (1986). can be manufactured.
本発明の方法を行うことにより得られる（２Ｒ，３Ｓ）−β−フェニルイソセリ ンは一般式： ［式中Ｒは水素原子又はアセチル基であり、Ｒ３はフェニル又はｔ−ブトキシ基 である］ のタキサン誘導体などの治療的活性生成物の合成を行うのに特に有用である。(2R,3S)-β-phenylisoserine obtained by carrying out the method of the present invention The general formula is: [In the formula, R is a hydrogen atom or an acetyl group, and R3 is a phenyl or t-butoxy group ] are particularly useful in carrying out the synthesis of therapeutically active products such as taxane derivatives.
ベンゾイル化剤（ベンゾイルクロリド）又はｔ−ブトキシカルボニル化剤（ｔ− ブチルジカーボネート）、及びその後ヒドロキシル官能基の保護のための試薬を 作用させることにより、β−フェニルイソセリンは一般式： ［式中Ｒ１はフェニル又はｔ−ブトキシ基であり、Ｚ、はヒドロキシル官能基の 原子団（１−エトキシエチル）を示す］の生成物を与える。Benzoylating agent (benzoyl chloride) or t-butoxycarbonylating agent (t- butyl dicarbonate), and then a reagent for the protection of the hydroxyl functionality. By acting, β-phenylisoserine has the general formula: [In the formula, R1 is a phenyl or t-butoxy group, and Z is a hydroxyl functional group. atomic group (1-ethoxyethyl)] to give the product.
一般式（Ｉ Ｉ Ｉ）の酸と、７−位及び場合により１〇−位のヒドロキシル官 能基が保護基（シリル、２． ２． ２−トリクロロエトキシカルボニル基）に より保護されているバッカチンＩＩＩ又は１０−デアセチルバラ力チンＴＩＥを 縮合させ、続いて保護基を水素原子で置換することにより一般式（Ｉ Ｉ）の生 成物が得られる。An acid of general formula (II) and a hydroxyl group at the 7-position and optionally the 10-position Functional group becomes a protecting group (silyl, 2.2.2-trichloroethoxycarbonyl group) The more protected baccatin III or 10-deacetylbalatatin TIE The product of general formula (II) can be produced by condensation and subsequent substitution of the protecting group with a hydrogen atom. A product is obtained.
一般式（Ｉ Ｉ Ｉ）の酸と保護バッカチンＩＩＩ又は保護１０−デアセチルバ ッカチンＩＩＩの縮合、ならびに水素を用いた保護基の置換は欧州特許ＥＰ−０ ，３３６，８４０又はＥＰ−０，３３６，８４１に記載の条件下で行うことがで きる。Acid of general formula (II) and protected baccatin III or protected 10-deacetylba The condensation of Katin III and the substitution of protecting groups with hydrogen are described in European Patent EP-0 , 336,840 or under the conditions described in EP-0,336,841. Wear.
以下の実施例は、制限を目的とせずに本発明の実行法を示すものである。The following examples illustrate, but are not intended to be limiting, how the invention may be carried out.
実施例１ ９８％で分析すると、エナンチオマー過剰（ｅｎａｎｔｉｏｍｅｒｉ（ｅｘｃｅ ｓｓ）が９８．５％を超えるα−メチルベンジルアミン（２Ｒ，３Ｒ）−β−フ ェニルグリシド酸塩３ｋｇ、及び１５リツトルの３２％（ｗ／ｗ）アンモニア溶 液をカラムに導入する。計量型ポンプを用い、３−５リットル／時間の流量でカ ラムの底部にトルエンを導入する。Example 1 When analyzed at 98%, enantiomeric excess (exce α-Methylbenzylamine (2R,3R)-β-phthalate with ss) exceeding 98.5% 3 kg of phenyl glycidate and 15 liters of 32% (w/w) ammonia solution Introduce the liquid into the column. Using a metering pump, pump at a flow rate of 3-5 liters/hour. Introduce toluene at the bottom of the ram.
カラムの頭部で分離するトルエン溶液をあふれさせて除去する。１８リツトルの トルエンを導入した後、トルエン抽出物中にα−メチルベンジルアミンは検出さ れない。The toluene solution separating at the head of the column is removed by flooding. 18 liters After introducing toluene, α-methylbenzylamine was not detected in the toluene extract. Not possible.
上記で得たアンモニウムβ−フェニルグリシド酸塩の溶液及び３０リツトルのオ ートクレーブに導入する。オートクレーブを密閉し、その後撹拌しながら１時間 かけて６０℃に加熱する。圧力は２．５バ一ル近辺である。６０℃で５時間撹拌 を続け、その後オートクレーブを１８℃に冷却する。２．５リツトルの水中の９ ｋｇの塩化ナトリウム及び０． ４２ｋｇの水酸化ナトリウムペレットの添加後 、アンモニアを減圧下（１００−７００ｍｍ水銀；１３．３−９３ｋＰａ）及び ２４℃にて蒸留することにより除去する。装置の圧力が４５ｍｍ水銀（６ｋ Ｐ ａ）に達したら、反応混合物を４８℃に加熱して塩を溶解し、その後−５から 一８℃の温度に３時間冷却する。The solution of ammonium β-phenylglyside obtained above and 30 liters of Introduce into the autoclave. Close the autoclave and then stir for 1 hour. Heat to 60°C. The pressure is around 2.5 bar. Stir at 60℃ for 5 hours Continue to cool the autoclave to 18°C. 9 in 2.5 liters of water kg of sodium chloride and 0.0 kg of sodium chloride. After adding 42 kg of sodium hydroxide pellets , ammonia under reduced pressure (100-700 mm mercury; 13.3-93 kPa) and Remove by distillation at 24°C. The pressure of the device is 45mm mercury (6kP Once a) is reached, the reaction mixture is heated to 48 °C to dissolve the salts and then from -5 to Cool to a temperature of -8°C for 3 hours.
得られた白色結晶を濾過により分離し、その後減圧下（１ｍｍ水銀；０．１３ｋ Ｐａ）の４０℃で乾燥する。それにより融点が２１８℃の（２Ｒ，３Ｓ）−β− フェニルイソセリンナトリウム塩（１９３２ｇ）が得られる。The obtained white crystals were separated by filtration and then purified under reduced pressure (1 mm mercury; 0.13 k Dry at 40°C in Pa). (2R,3S)-β- with a melting point of 218°C. Phenyl isoserine sodium salt (1932 g) is obtained.
重水中、９０ＭＨｚで決定した（２Ｒ，３Ｓ）〜β−フェニルイソセリンナトリ ウム塩のＩ３０核磁気共鳴スペクトルは以下の化学シフトを特徴とする（δ）： ６０．２ （’ＪＣＨ＝１４０Ｈｚ）：８０．Ｏ（’ＪＣＨ＝１４７Ｈｚ；２Ｊ ＝２．６Ｈｚ）；１２９．６；１３０．２；１．３１．５；１４４．４及び１８ １．６ｐｐｍ。(2R,3S) ~ β-phenylisoserine sodium determined at 90 MHz in heavy water The I30 nuclear magnetic resonance spectrum of the salt is characterized by the following chemical shifts (δ): 60.2 ('JCH=140Hz):80. O('JCH=147Hz; 2J =2.6Hz); 129.6; 130.2; 1.31.5; 144.4 and 18 1.6ppm.
実施例２ １０ｋｇのα−メチルベンジルアミン（２Ｒ，３Ｒ）−β−フェニルグリシド酸 塩（３５，０８モル）、１５リツトルの水及び２０リツトルのトルエンを２５０ リツトルの反応器に導入し、その後２０℃近辺の温ベンジルアミンを含むトルエ ン相を保持する。水相を１０リツトルのトルエンで２回洗浄し、すべてのα−メ チルベンジルアミンを除去する。Example 2 10 kg α-methylbenzylamine (2R,3R)-β-phenylglycidic acid salt (35.08 mol), 15 liters of water and 20 liters of toluene to 250 Toluene containing benzylamine at around 20°C is then introduced into a small reactor. hold the phase. Wash the aqueous phase twice with 10 liters of toluene to remove all α-methane. Remove tilbenzylamine.
合わせたトルエン相からα−メチルベンジルアミンを単離することができ゛る。α-Methylbenzylamine can be isolated from the combined toluene phases.
１．８６０ｋｇの塩化アンモニウム及び１６２リツトルの２０％（Ｗ／Ｖ）アン モニア溶液を、２５０リツトルの反応器に入れた水相に加える。混合物を５０℃ に加熱し、１７時間撹拌を続ける。３５℃に冷却後、３５ｋｇの塩化ナトリウム を加え、その後混合物をこの温度に３０分間保つ。それをゆっくり（２時間）０ −５℃の温度に冷却し、その後この温度に１時間保つ。沈澱を濾過により分離し 、その後５０℃の減圧下で乾燥する。それにより７ｋｇの乾燥生成物が得られ、 その生成物は約２５％の塩化ナトリウム及び約５．３００ｋｇの純粋な（２Ｒ， ３Ｓ）−β−フェニルイソセリンナトリウム塩を含む。1.860 kg of ammonium chloride and 162 liters of 20% (w/v) ammonium The monia solution is added to the aqueous phase in a 250 liter reactor. Mixture at 50℃ and continue stirring for 17 hours. After cooling to 35°C, 35 kg of sodium chloride is added and then the mixture is kept at this temperature for 30 minutes. Do it slowly (2 hours)0 Cool to a temperature of -5°C and then keep at this temperature for 1 hour. Separate the precipitate by filtration , and then dried under reduced pressure at 50°C. 7 kg of dry product was thereby obtained, The product contains about 25% sodium chloride and about 5.300 kg of pure (2R, 3S)-β-phenylisoserine sodium salt.
収率は７２％である。Yield is 72%.
かくして得られた生成物は、さらに処理することなくその後の合成で用いること ができる。The product thus obtained can be used in subsequent syntheses without further treatment. Can be done.
国際調査報告 一一一一〜−−−− Ｋテｌ陀９２／αカ３２international search report 1111～---K Tel 92/α Ka 32
Claims (10)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9100491A FR2671799B1 (en) | 1991-01-17 | 1991-01-17 | B-PHENYLISOSERINE- (2R, 3S), ITS SALTS, ITS PREPARATION AND ITS USE. |
| FR91/00491 | 1991-01-17 | ||
| PCT/FR1992/000032 WO1992012958A1 (en) | 1991-01-17 | 1992-01-16 | β-PHENYLISOSERINE-(2R,3S), SALTS, PREPARATION AND USE THEREOF |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06504549A true JPH06504549A (en) | 1994-05-26 |
| JP3233632B2 JP3233632B2 (en) | 2001-11-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50400792A Expired - Fee Related JP3233632B2 (en) | 1991-01-17 | 1992-01-16 | (2R, 3S) -β-phenylisoserine, salt thereof, production and use thereof |
Country Status (25)
| Country | Link |
|---|---|
| EP (2) | EP0495718A1 (en) |
| JP (1) | JP3233632B2 (en) |
| KR (1) | KR100235372B1 (en) |
| AT (1) | ATE157081T1 (en) |
| AU (1) | AU651669B2 (en) |
| CA (1) | CA2099783C (en) |
| CZ (1) | CZ281266B6 (en) |
| DE (1) | DE69221733T3 (en) |
| DK (1) | DK0603176T4 (en) |
| ES (1) | ES2104895T5 (en) |
| FI (1) | FI113641B (en) |
| FR (1) | FR2671799B1 (en) |
| GR (1) | GR3024533T3 (en) |
| HU (1) | HU213616B (en) |
| IE (1) | IE920127A1 (en) |
| MX (1) | MX9200181A (en) |
| NO (1) | NO303539B1 (en) |
| NZ (1) | NZ241312A (en) |
| PL (1) | PL167676B1 (en) |
| RU (1) | RU2090551C1 (en) |
| SK (1) | SK281140B6 (en) |
| TW (1) | TW221413B (en) |
| WO (1) | WO1992012958A1 (en) |
| YU (1) | YU48153B (en) |
| ZA (1) | ZA92317B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5646176A (en) | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
| TW467896B (en) | 1993-03-19 | 2001-12-11 | Bristol Myers Squibb Co | Novel β-lactams, methods for the preparation of taxanes and sidechain-bearing taxanes |
| WO2003047508A2 (en) | 2001-11-30 | 2003-06-12 | Bristol-Myers Squibb Company | Paclitaxel solvates |
| US20200005163A1 (en) | 2017-02-10 | 2020-01-02 | Nec Corporation | Inference-use knowledge generation apparatus, inference-use knowledge generation method, and computer-readable recording medium |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2629818B1 (en) † | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | PROCESS FOR THE PREPARATION OF TAXOL |
| FR2629819B1 (en) † | 1988-04-06 | 1990-11-16 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF BACCATIN III AND DESACETYL-10 BACCATIN III DERIVATIVES |
| IL95436A (en) † | 1989-08-23 | 1996-07-23 | Centre Nat Rech Scient | Method for the preparation of phenzlisoserine derivatives |
-
1991
- 1991-01-17 FR FR9100491A patent/FR2671799B1/en not_active Expired - Lifetime
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1992
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- 1992-01-16 KR KR1019930702148A patent/KR100235372B1/en not_active IP Right Cessation
- 1992-01-16 CA CA002099783A patent/CA2099783C/en not_active Expired - Lifetime
- 1992-01-16 IE IE012792A patent/IE920127A1/en not_active IP Right Cessation
- 1992-01-16 TW TW081100266A patent/TW221413B/zh not_active IP Right Cessation
- 1992-01-16 PL PL92299833A patent/PL167676B1/en unknown
- 1992-01-16 EP EP92400112A patent/EP0495718A1/en active Pending
- 1992-01-16 RU RU9293051781A patent/RU2090551C1/en active
- 1992-01-16 ZA ZA92317A patent/ZA92317B/en unknown
- 1992-01-16 DK DK92904034T patent/DK0603176T4/en active
- 1992-01-16 CZ CS931390A patent/CZ281266B6/en not_active IP Right Cessation
- 1992-01-16 AT AT92904034T patent/ATE157081T1/en not_active IP Right Cessation
- 1992-01-16 WO PCT/FR1992/000032 patent/WO1992012958A1/en active IP Right Grant
- 1992-01-16 ES ES92904034T patent/ES2104895T5/en not_active Expired - Lifetime
- 1992-01-16 HU HU9302064A patent/HU213616B/en unknown
- 1992-01-16 SK SK746-93A patent/SK281140B6/en not_active IP Right Cessation
- 1992-01-16 DE DE69221733T patent/DE69221733T3/en not_active Expired - Lifetime
- 1992-01-16 EP EP92904034A patent/EP0603176B2/en not_active Expired - Lifetime
- 1992-01-16 JP JP50400792A patent/JP3233632B2/en not_active Expired - Fee Related
- 1992-01-16 MX MX9200181A patent/MX9200181A/en active IP Right Grant
- 1992-01-16 AU AU12237/92A patent/AU651669B2/en not_active Expired
- 1992-01-17 YU YU5492A patent/YU48153B/en unknown
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1993
- 1993-07-06 NO NO932458A patent/NO303539B1/en not_active IP Right Cessation
- 1993-07-16 FI FI933249A patent/FI113641B/en active
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1997
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